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Disease Severity and Effective Parasite Multiplication Rate in Falciparum Malaria
Abstract Patients presenting with severe falciparum malaria in a Bangladeshi tertiary hospital had higher total parasite burden, estimated by parasitemia and plasma PfHRP2, than uncomplicated malaria patients despite shorter fever duration. This suggests that higher parasite multiplication rates (PMR) contribute to causing the higher biomass found in severe disease. Compared with patients without a history of previous malaria, patients with previous malaria carried a lower parasite biomass with similar fever duration at presentation, suggesting that host immunity reduces the PMR.
The role of previously unmeasured organic acids in the pathogenesis of severe malaria
Abstract Introduction Severe falciparum malaria is commonly complicated by metabolic acidosis. Together with lactic acid (LA), other previously unmeasured acids have been implicated in the pathogenesis of falciparum malaria. Methods In this prospective study, we characterised organic acids in adults with severe falciparum malaria in India and Bangladesh. Liquid chromatography-mass spectrometry was used to measure organic acids in plasma and urine. Patients were followed until recovery or death. Results Patients with severe malaria (n=138), uncomplicated malaria (n=102), sepsis (n=32) and febrile encephalopathy (n=35) were included. Strong ion gap (mean±SD) was elevated in severe malaria (8.2 mEq/L±4.5) and severe sepsis (8.6 mEq/L±7.7) compared with uncomplicated malaria (6.0 mEq/L±5.1) and encephalopathy (6.6 mEq/L±4.7). Compared with uncomplicated malaria, severe malaria was characterised by elevated plasma LA, hydroxyphenyllactic acid (HPLA), α-hydroxybutyric acid and β-hydroxybutyric acid (all P<0.05). In urine, concentrations of methylmalonic, ethylmalonic and α-ketoglutaric acids were also elevated. Multivariate logistic regression showed that plasma HPLA was a strong independent predictor of death (odds ratio [OR] 3.5, 95 % confidence interval [CI] 1.6–7.5, P=0.001), comparable to LA (OR 3.5, 95 % CI 1.5–7.8, P=0.003) (combined area under the receiver operating characteristic curve 0.81). Conclusions Newly identified acids, in addition to LA, are elevated in patients with severe malaria and are highly predictive of fatal outcome. Further characterisation of their sources and metabolic pathways is now needed.
Acetaminophen as a Renoprotective Adjunctive Treatment in Patients With Severe and Moderately Severe Falciparum Malaria: A Randomized, Controlled, Open-Label Trial
This randomized, controlled trial shows that acetaminophen reduces kidney dysfunction and risk of developing acute kidney injury, particularly in severe malaria patients who present with high plasma hemoglobin, supporting the hypothesis that acetaminophen inhibits cell-free hemoglobin-mediated renal tubular oxidative damage.
The predictive capacity of biomarkers for clinical pulmonary oedema in patients with severe falciparum malaria is low: a prospective observational study.
BackgroundPulmonary oedema is a feared and difficult to predict complication of severe malaria that can emerge after start of antimalarial treatment. Proinflammatory mediators are thought to play a central role in its pathogenesis.MethodsAn exploratory study was conducted to evaluate the predictive capacity of biomarkers for development of clinical pulmonary oedema in patients with severe falciparum malaria at two hospitals in Bangladesh. Plasma concentrations of interleukin-6 (IL-6), IL-8, tumour necrosis factor (TNF), soluble Receptor of Advanced Glycation End-products (sRAGE), surfactant protein-D (SP-D), club cell secretory protein (CC16), and Krebs von den Lungen-6 (KL-6) on admission were compared with healthy controls. Correlations between these biomarker and plasma lactate and Plasmodium falciparum histidine-rich protein 2 (PfHRP2) levels were evaluated. Receiver Operating Characteristic (ROC) curves were constructed to assess the predictive capacity for clinical pulmonary oedema of the biomarkers of interest.ResultsOf 106 screened patients with falciparum malaria, 56 were classified as having severe malaria with a mortality rate of 29%. Nine (16%) patients developed clinical pulmonary oedema after admission. Plasma levels of the biomarkers of interest were higher in patients compared to healthy controls. IL-6, IL-8, TNF, sRAGE, and CC16 levels correlated well with plasma PfHRP2 levels (rs = 0.39; P = 0.004, rs = 0.43; P = 0.001, rs = 0.54; P s = 0.44; P s = 0.43; P = 0.001, respectively). Furthermore, IL-6 and IL-8 levels correlated well with plasma lactate levels (rs = 0.37; P = 0.005, rs = 0.47; P ConclusionsIL-6, IL-8, TNF, sRAGE, SP-D, CC16 and KL-6 cannot be used in predicting clinical pulmonary oedema in severe malaria patients.
Family participation to enhance care and tackle health worker shortages in resource-limited hospitals: A systematic review.
BackgroundA growing global shortage of health workers is limiting access to health care, especially in resource-limited countries. Family participation in hospital care could enhance care while tackling health worker shortages. With the same resources, it might deliver additional and more personalised care. This review assessed the effect and safety of family participation interventions in the care of hospitalised adults in resource-limited settings and, ultimately, if it is a viable strategy to tackle health worker shortages.MethodsFor this systematic review, Medline, Embase, CINAHL and the Global Health Library were searched from inception till April 7, 2022. Clinical studies were included if they described a family participation intervention for hospitalised adults, were performed in a low- or middle-income country and reported on a patient-related outcome. Data were collected on patient, family, staff and health service-related outcomes. Risk of bias was assessed with the ROB2 and ROBINS-I tool.ResultsFrom 4444 studies, six were included for narrative synthesis, with a total of 1794 participants. Four studies were performed in Asia and two in Africa; all were published between 2017 and 2022. In-hospital family participation interventions aimed at medication administration and adherence, delirium prevention, and palliative cancer care were successful in significantly improving patient outcomes. Involving family in post-stroke rehabilitation interventions showed no significant effect on mortality and long-term disability. Few data were reported on participating family members' outcomes or hospital staffing issues. None of the included studies showed harm from family participation.ConclusionsThe limited data suggest that family participation can be effective and safe in specific contexts. However, more research is needed to determine the effect of family participation and justify further implementation. Family participation research for enhancing care while tackling health worker shortages should be a collaborative priority of researchers, health care professionals, funding agencies and policymakers.RegistrationPROSPERO registration No. CRD42020205878.
Point-of-care ultrasound to assess volume status and pulmonary oedema in malaria patients.
PurposeFluid management is challenging in malaria patients given the risks associated with intravascular fluid depletion and iatrogenic fluid overload leading to pulmonary oedema. Given the limitations of the physical examination in guiding fluid therapy, we evaluated point-of-care ultrasound (POCUS) of the inferior vena cava (IVC) and lungs as a novel tool to assess volume status and detect early oedema in malaria patients.MethodsTo assess the correlation between IVC and lung ultrasound (LUS) indices and clinical signs of hypovolaemia and pulmonary oedema, respectively, concurrent clinical and sonographic examinations were performed in an observational study of 48 malaria patients and 62 healthy participants across age groups in Gabon.ResultsIVC collapsibility index (CI) ≥ 50% on enrolment reflecting intravascular fluid depletion was associated with an increased number of clinical signs of hypovolaemia in severe and uncomplicated malaria. With exception of dry mucous membranes, IVC-CI correlated with most clinical signs of hypovolaemia, most notably sunken eyes (r = 0.35, p = 0.0001) and prolonged capillary refill (r = 0.35, p = 0.001). IVC-to-aorta ratio ≤ 0.8 was not associated with any clinical signs of hypovolaemia on enrolment. Among malaria patients, a B-pattern on enrolment reflecting interstitial fluid was associated with dyspnoea (p = 0.0003), crepitations and SpO2 ≤ 94% (both p ConclusionIn malaria patients, POCUS of the IVC and lungs may improve the assessment of volume status and detect early oedema, which could help to manage fluids in these patients.
Antimicrobial drug resistance among clinically relevant bacterial isolates in sub-Saharan Africa: a systematic review.
BackgroundLittle is known about the prevalence of antimicrobial resistance (AMR) amongst bacterial pathogens in sub-Saharan Africa (sSA), despite calls for continent-wide surveillance to inform empirical treatment guidelines.MethodsWe searched PubMed and additional databases for susceptibility data of key pathogens for surveillance, published between 1990 and 2013. Extracted data were standardized to a prevalence of resistance in populations of isolates and reported by clinical syndrome, microorganism, relevant antimicrobial drugs and region.ResultsWe identified 2005 publications, of which 190 were analysed. Studies predominantly originated from east sSA (61%), were hospital based (60%), were from an urban setting (73%) and reported on isolates from patients with a febrile illness (42%). Quality procedures for susceptibility testing were described in <50% of studies. Median prevalence (MP) of resistance to chloramphenicol in Enterobacteriaceae, isolated from patients with a febrile illness, ranged between 31.0% and 94.2%, whilst MP of resistance to third-generation cephalosporins ranged between 0.0% and 46.5%. MP of resistance to nalidixic acid in Salmonella enterica Typhi ranged between 15.4% and 43.2%. The limited number of studies providing prevalence data on AMR in Gram-positive pathogens or in pathogens isolated from patients with a respiratory tract infection, meningitis, urinary tract infection or hospital-acquired infection suggested high prevalence of resistance to chloramphenicol, trimethoprim/sulfamethoxazole and tetracycline and low prevalence to third-generation cephalosporins and fluoroquinolones.ConclusionsOur results indicate high prevalence of AMR in clinical bacterial isolates to antimicrobial drugs commonly used in sSA. Enhanced approaches for AMR surveillance are needed to support empirical therapy in sSA.
Host innate immune responses to sepsis.
The immune response to sepsis can be seen as a pattern recognition receptor-mediated dysregulation of the immune system following pathogen invasion in which a careful balance between inflammatory and anti-inflammatory responses is vital. Invasive infection triggers both pro-inflammatory and anti-inflammatory host responses, the magnitude of which depends on multiple factors, including pathogen virulence, site of infection, host genetics, and comorbidities. Toll-like receptors, the inflammasomes, and other pattern recognition receptors initiate the immune response after recognition of danger signals derived from microorganisms, so-called pathogen-associated molecular patterns or derived from the host, so-called danger-associated molecular patterns. Further dissection of the role of host-pathogen interactions, the cytokine response, the coagulation cascade, and their multidirectional interactions in sepsis should lead toward the development of new therapeutic strategies in sepsis.
Common bile duct dilatation in drug users with chronic hepatitis C is associated with current methadone use.
ObjectivesDilatation of the common bile duct (CBD) can be an ominous sign for malignancy of the pancreatobiliary tract; however, it has also been described as a presumably harmless side effect of opioid use. We investigated the prevalence and determinants of CBD dilatation among drug users receiving methadone maintenance therapy in the Netherlands.MethodsA cross-sectional study was conducted in a prospectively studied and well-defined cohort of drug users with chronic hepatitis C virus infection, attending the Public Health Service of Amsterdam, the Netherlands. Patients underwent abdominal ultrasonography as part of pretreatment screening. A multivariable logistic regression model was used to analyze potential demographic and drug use-related determinants of radiological CBD dilatation.ResultsBetween September 2004 and December 2011, 222 hepatitis C virus-infected drug users were evaluated. Dilatation of the CBD was found in 50 of 222 patients (22.5%), with a median diameter of 8.0 mm (interquartile range, 7.0 to 10.0; n = 43). Dilatation was associated with current use of methadone (adjusted odds ratio = 20.50; 95% confidence interval, 2.79 to 2.61 × 10(3)), independent of the current methadone dose, and with age per 10-year increase (adjusted odds ratio = 1.68; 95% confidence interval, 1.06 to 2.71). Regular use of heroin in the 6 months before ultrasonography was not found to be associated with dilatation.ConclusionsDilatation of the CBD is common in drug users under methadone treatment and seems to be a harmless side effect of opioid agonists.
Lung Ultrasound for Detection of Pulmonary Complications in Critically Ill Obstetric Patients in a Resource-Limited Setting.
Critically ill parturients have an increased risk of developing pulmonary complications. Lung ultrasound (LUS) could be effective in addressing the cause of respiratory distress in resource-limited settings with high maternal mortality. We aimed to determine the frequency, timing of appearance, and type of pulmonary complications in critically ill parturients in an obstetric unit in Sierra Leone. In this prospective observational study, LUS examinations were performed on admission, after 24 and 48 hours, and in case of respiratory deterioration. Primary endpoint was the proportion of parturients with one or more pulmonary complications, stratified for the presence of respiratory distress. Secondary endpoints included timing and types of complications, and their association with "poor outcome," defined as a composite of transfer for escalation of care or death. Of 166 patients enrolled, 35 patients (21% [95% CI: 15-28]) had one or more pulmonary complications, the majority diagnosed on admission. Acute respiratory distress syndrome (period prevalence 4%) and hydrostatic pulmonary edema (4%) were only observed in patients with respiratory distress. Pneumonia (2%), atelectasis (10%), and pleural effusion (7%) were present, irrespective of respiratory distress. When ultrasound excluded pulmonary complications, respiratory distress was related to anemia or metabolic acidosis. Pulmonary complications were associated with an increased risk of poor outcome (odds ratio: 5.0; 95% CI: 1.7-14.6; P = 0.003). In critically ill parturients in a resource-limited obstetric unit, LUS contributed to address the cause of respiratory distress by identifying or excluding pulmonary complications. These were associated with a poor outcome.